EGFR抑制剂.ppt

EGFR signal transduction in tumour cells * Epidermal Growth Factor Receptor (EGFR) Inhibitors Dr.M.Jayanthi Introduction Cellular Signalling Pathways Vital for cell cycle progression, growth, differentiation death. Growth Factors – The key stone A delicate balance between activating and inhibitory signals needs to be maintained normally Alteration in this balance - Dysregulated cellular proliferation survival of abnormal cells. Gene Transcription G0 G1 Priming S G2 M Cell Cycle Growth Factors + Growth Factors Cell Cycle Receptors Epidermal Growth Factor Receptor (EGFR) Breast 14 % - 91 % Colon 25 % - 77 % Lung Cancer 40 % - 80 % (Non small cell) Ovarian 35 % - 70 % Pancreatic 30 % - 50 % Head Neck 80 % - 95 % EGFR Expression Rate Tumour Some Landmarks in EGFR Signalling Stanley Cohen Human EGF (1970’s) Isolation and cloning of EGFR (1980’s). Link between EGFR and malignant transformation of cells demonstrated EGF in mice (1960’s) Mendelsohn et al., Blocking EGFR signalling to treat cancer Murine monoclonal antibodies targeting EGFR-TK→ Human:murine chimeric version More than 20 anti-EGFR agents in development TK TK TK erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 No specific ligands - often acts as dimer partner Heregulins NRG2 NRG3 Heregulins β-cellulin EGF, TGFa , b Cellulin Amphiregulin, HB-EGF Human Epidermal Growth Factor Receptor Family TK Intracellular Domain Transmembrane Domain Extracellular Domain EGFR Structure TK TK TK TK erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 EGFR Homo Dimerisation EGFR Stimulation dimerisation TK TK TK erbB1HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4 Hetero Dimerisation Risk for cancer EGFR stimul